Complexes of Zinc-Coordinated Heteroaromatic N-Oxides with Pyrene: Lewis Acid Effects on the Multicenter Donor–Acceptor Bonding

4-Nitroquinoline-N-oxide (NQO) and 4-nitropyridine-N-oxide (NPO) are important precursors for the synthesis of substituted heterocycles while NQO is a popular model mutagen and carcinogen broadly used in cancer research; intermolecular interactions are critical for their reactions or functioning in vivo. Herein, the effects of the coordination of N-oxide’s oxygen atom to Lewis acids on multicenter donor–acceptor bonding were explored via a combination of experimental and computational studies of the complexes of NQO and NPO with a typical π-electron donor, pyrene. Coordination with ZnCl2 increased the positive electrostatic potentials on the surfaces of these π-acceptors and lowered the energy of their LUMO. Analogous effects were observed upon the protonation of the N-oxides’ oxygen or bonding with boron trifluoride. The interaction of ZnCl2, NPO, or NQO and pyrene resulted in the formation of dark co-crystals comprising π-stacked Zn-coordinated N-oxides and pyrene similar to that found with protonated or (reported earlier) BF3-bonded N-oxides. Computational studies indicated that the coordination of N-oxides to zinc(II), BF3, or protonation led to the strengthening of the multicenter bonding of the nitro-heterocycle with pyrene, and this effect was related both to the increased electrostatic attraction and molecular–orbital interactions in their complexes.


Introduction
Heteroaromatic N-oxides have attracted significant attention from the scientific community due to their extensive synthetic applications and biological activity [1][2][3].Depending on the nature of the functional group in the heterocycle, the N-oxide group can exhibit electron-donating or electron-withdrawing effects, and therefore heteroaromatic N-oxides are more active in both aromatic electrophilic and nucleophilic substitution reactions than their parent heterocycles.Nitro-substituted N-oxides, 4-nitropyridine-N-oxide, NPO, and 4-nitroquinoline-N-oxide, NQO (Scheme 1) are of special interest in this respect.These substances can be easily obtained from their corresponding pyridine and quinoline N-oxides by nitration, and the nitro group is relatively easily converted into other functional groups leading to a wide variety of substituted heterocycles [2,4].
Besides their synthetic significance, the nitro-derivatives of heteroaromatic N-oxides, especially 4-nitroquinoline-N-oxide, are characterized by strong biological activity.Since the discovery of the mutagenic and carcinogenic activity of NQO in the 1950s (soon after its first preparation), this molecule became a popular model carcinogen and mutagen agent used for the study of carcinogenesis mechanisms, artificial tumorigenesis, and mutant organism production [5][6][7].Besides their synthetic significance, the nitro-derivatives of heteroaromatic N-oxides, especially 4-nitroquinoline-N-oxide, are characterized by strong biological activity.Since the discovery of the mutagenic and carcinogenic activity of NQO in the 1950s (soon after its first preparation), this molecule became a popular model carcinogen and mutagen agent used for the study of carcinogenesis mechanisms, artificial tumorigenesis, and mutant organism production [5][6][7].
The presence of the nitro group makes NQO and NPO molecules mild electron πacceptors (π-acid) suitable for the charge-transfer interactions with planar aromatic electron donors (π-bases) [8,9].The formation of charge-transfer complexes with DNA and proteins is considered an important factor in the biological action of NQO [10][11][12].On the other hand, the oxygen atoms in the N-oxide groups are well-suited to interact with Lewis acids [8,[13][14][15].Our earlier spectral and structural studies showed that the coordination of this oxygen to boron trifluoride facilitates the formation of π-π bonded complexes of N-oxides with planar organic donors in the solid state and solutions [8].Such coordination also substantially enhanced the electron-acceptor properties of the N-oxides, and it facilitated the oxidation of many organic donors (which did not proceed without the Lewis acid) [8].A computational study by Frontera et al. showed that the halogen, hydrogen, or triel bonding or coordination of the oxygen to a metal ion enhanced the positive potential (π-hole) on the surface of NPO above the C-NO2 fragment and, therefore, strengthened the interaction between the N-oxide and various bases [15].It was also shown that interaction with the Lewis acids substantially accelerates the SNAr reactions of N-oxides [16][17][18][19].
The major effects of boron trifluoride on the interaction of N-oxides with organic donors and their redox reactions suggested that Lewis acids could be an important factor controlling the chemical transformations of these molecules and their behavior in living cells.However, while BF3 is a common reagent for organic synthesis, its high reactivity precludes its presence or use in biological systems.This raises the question about the effects of other Lewis acids on the intermolecular interactions of aromatic N-oxides, in particular the formation of π-stacked donor-acceptor complexes.Such bonding affects the reactivity of N-oxides [17], and the formation of such complexes is of significant interest for the co-crystallization of pharmaceutical compounds as well as non-linear optical and other materials' science applications [20][21][22][23].Thus, in the current work, we explored the effects of the coordination of NQO and NPO to zinc chloride and their protonation on the interaction of these N-oxides with a common organic π-donor, pyrene.Indeed, zinc ions and protons are very common Lewis acids that are found in many chemical and/or biological systems.Furthermore, the crystallographic literature comprises many structures of N-oxide molecules coordinated to zinc(II) halides (or other divalent cations) [24][25][26][27].Such complexes showed interesting catalytic properties [28].There are also several structures showing protonated N-oxide molecules (which frequently form hydrogen-bonded dimers with more or less symmetric O-H-O fragments) [29][30][31].However, there are essentially no data about the effects of such zinc coordination or protonation on the properties of the nitro substituted N-oxides or the interactions of the latter with organic π-donors in solution or the solid states.
Accordingly, we report herein the results of the structural characterization of co-crys- The presence of the nitro group makes NQO and NPO molecules mild electron πacceptors (π-acid) suitable for the charge-transfer interactions with planar aromatic electron donors (π-bases) [8,9].The formation of charge-transfer complexes with DNA and proteins is considered an important factor in the biological action of NQO [10][11][12].On the other hand, the oxygen atoms in the N-oxide groups are well-suited to interact with Lewis acids [8,[13][14][15].Our earlier spectral and structural studies showed that the coordination of this oxygen to boron trifluoride facilitates the formation of π-π bonded complexes of Noxides with planar organic donors in the solid state and solutions [8].Such coordination also substantially enhanced the electron-acceptor properties of the N-oxides, and it facilitated the oxidation of many organic donors (which did not proceed without the Lewis acid) [8].A computational study by Frontera et al. showed that the halogen, hydrogen, or triel bonding or coordination of the oxygen to a metal ion enhanced the positive potential (π-hole) on the surface of NPO above the C-NO 2 fragment and, therefore, strengthened the interaction between the N-oxide and various bases [15].It was also shown that interaction with the Lewis acids substantially accelerates the S N Ar reactions of N-oxides [16][17][18][19].
The major effects of boron trifluoride on the interaction of N-oxides with organic donors and their redox reactions suggested that Lewis acids could be an important factor controlling the chemical transformations of these molecules and their behavior in living cells.However, while BF 3 is a common reagent for organic synthesis, its high reactivity precludes its presence or use in biological systems.This raises the question about the effects of other Lewis acids on the intermolecular interactions of aromatic N-oxides, in particular the formation of π-stacked donor-acceptor complexes.Such bonding affects the reactivity of N-oxides [17], and the formation of such complexes is of significant interest for the co-crystallization of pharmaceutical compounds as well as non-linear optical and other materials' science applications [20][21][22][23].Thus, in the current work, we explored the effects of the coordination of NQO and NPO to zinc chloride and their protonation on the interaction of these N-oxides with a common organic π-donor, pyrene.Indeed, zinc ions and protons are very common Lewis acids that are found in many chemical and/or biological systems.Furthermore, the crystallographic literature comprises many structures of N-oxide molecules coordinated to zinc(II) halides (or other divalent cations) [24][25][26][27].Such complexes showed interesting catalytic properties [28].There are also several structures showing protonated N-oxide molecules (which frequently form hydrogen-bonded dimers with more or less symmetric O-H-O fragments) [29][30][31].However, there are essentially no data about the effects of such zinc coordination or protonation on the properties of the nitro substituted N-oxides or the interactions of the latter with organic π-donors in solution or the solid states.
Accordingly, we report herein the results of the structural characterization of cocrystals comprising π-π bonded associations between zinc-coordinated or protonated N-oxides and pyrenes, as well as the results of experimental and computational studies on the effects of the bonding with ZnCl 2 or protons on the properties of the nitro-substituted N-oxides, and on the multicenter donor-acceptor bonding.Comparison with previously reported data about similar systems with boron trifluoride allows us to elucidate the general effects of Lewis acid on the intermolecular multicenter interactions of the heteroaromatic N-oxides with organic π-donors.

UV-Vis Measurements of Coordination of N-Oxides to Zinc(II) in Solutions
To evaluate the propensity of zinc(II) to coordinate to heteroaromatic N-oxides, we first carried out the UV-Vis measurements of their interaction in solutions.An addition of ZnCl 2 to a solution of heteroaromatic N-oxides in acetonitrile resulted in a decrease in the intensity of the absorption bands of the N-oxide molecule and the appearance of new bands at lower wavelengths (Figure 1 and Figure S1 in the Supporting Information).
N-oxides, and on the multicenter donor-acceptor bonding.Comparison with previously reported data about similar systems with boron trifluoride allows us to elucidate the general effects of Lewis acid on the intermolecular multicenter interactions of the heteroaromatic N-oxides with organic π-donors.

UV-Vis Measurements of Coordination of N-Oxides to Zinc(II) in Solutions
To evaluate the propensity of zinc(II) to coordinate to heteroaromatic N-oxides, we first carried out the UV-Vis measurements of their interaction in solutions.An addition of ZnCl2 to a solution of heteroaromatic N-oxides in acetonitrile resulted in a decrease in the intensity of the absorption bands of the N-oxide molecule and the appearance of new bands at lower wavelengths (Figure 1 and Figure S1 in the Supporting Information).A similar appearance of blue-shifted absorption bands was observed upon the protonation of the N-oxides (see Figure S2 in the Supporting Information).Also, analogous spectral changes were reported earlier upon the addition of BF3 [8].
The UV-Vis measurements with different N-oxides showed that the strength of their bonding with zinc(II) is related to the basicity of the N-oxide oxygens which is determined by the electron-withdrawing or donating abilities of the substituents [32].Indeed, the addition of ZnCl2 to the pyridine-N-oxide (Figure 1) or its p-methoxy substituted analogs (Figure S1) in a 1:2 molar ratio resulted in the essentially complete disappearance of the original absorption bands of the N-oxide molecule and the formation of new bands.This suggests strong 2:1 bonding of these N-oxides to zinc(II).In comparison, a substantial amount of the uncoordinated NPO and NQO molecules remain in solutions even after the addition of a large excess of ZnCl2 (Figure 1 and Figure S1 in the Supporting Information).This trend is similar to that observed upon the addition of HPF6 to the solution of various N-oxides, as well as an earlier reported variation in the formation constants of the halogen-bonded complexes of diiodine with these molecules [13,14,33].(Note that the determinations of the formation constants of 1:1 and 1:2 complexes of zinc(II) with N-oxides would require additional investigations that are beyond the scope of the current manuscript.) An addition of pyrene to the solutions containing nitro-substituted N-oxides in acetonitrile, dichloromethane, or THF resulted in a change in color from yellow to orange (Figure S3 in the Supporting Information).Earlier studies related these spectral changes to the formation of charge-transfer complexes between the π-acceptors (NPO or NQO) A similar appearance of blue-shifted absorption bands was observed upon the protonation of the N-oxides (see Figure S2 in the Supporting Information).Also, analogous spectral changes were reported earlier upon the addition of BF 3 [8].
The UV-Vis measurements with different N-oxides showed that the strength of their bonding with zinc(II) is related to the basicity of the N-oxide oxygens which is determined by the electron-withdrawing or donating abilities of the substituents [32].Indeed, the addition of ZnCl 2 to the pyridine-N-oxide (Figure 1) or its p-methoxy substituted analogs (Figure S1) in a 1:2 molar ratio resulted in the essentially complete disappearance of the original absorption bands of the N-oxide molecule and the formation of new bands.This suggests strong 2:1 bonding of these N-oxides to zinc(II).In comparison, a substantial amount of the uncoordinated NPO and NQO molecules remain in solutions even after the addition of a large excess of ZnCl 2 (Figure 1 and Figure S1 in the Supporting Information).This trend is similar to that observed upon the addition of HPF 6 to the solution of various N-oxides, as well as an earlier reported variation in the formation constants of the halogen-bonded complexes of diiodine with these molecules [13,14,33].(Note that the determinations of the formation constants of 1:1 and 1:2 complexes of zinc(II) with N-oxides would require additional investigations that are beyond the scope of the current manuscript).
An addition of pyrene to the solutions containing nitro-substituted N-oxides in acetonitrile, dichloromethane, or THF resulted in a change in color from yellow to orange (Figure S3 in the Supporting Information).Earlier studies related these spectral changes to the formation of charge-transfer complexes between the π-acceptors (NPO or NQO) and the π-donor, pyrene [8].The addition of ZnCl 2 to these solutions resulted in an immediate change in the color to brown-red.(Figure S3 in the Supporting Information).Similar color changes were observed earlier upon the addition of pyrene to the solutions of BF 3 -coordinated NPO and NQO molecules, and they were related to the formation of charge-transfer complexes between BF 3 -coordinated NPO or NQO and pyrene.These complexes showed absorption bands in the 500-600 nm range (which are red-shifted as compared to those of the corresponding complexes with individual N-oxides) [8].TD DFT calculations indicated the presence of equivalent low-energy absorption bands for the complexes of protonated and Zn(II)-coordinated NQO (Table S1 in the Supporting Information).However, the presence of uncoordinated N-oxides in the solution with the highest concentrations of ZnCl 2 together with the low solubility of pyrene in solvents suitable for the dissolution of zinc chloride precluded a quantitative UV-Vis spectral measurements of the interaction of Zn-coordinated N-oxides with pyrene.As such, the new absorption band of such complexes was observed only in the solutions of protonated NQO (Figure S4 in the Supporting Information).Overall, the liquid-phase studies indicated that despite the presence of an electron-withdrawing substituent, NPQ and NQO form complexes with ZnCl 2 , and the presence of the latter affects the interaction between N-oxides and pyrene in a similar way as boron trifluoride.

X-ray Structural Studies of the Associations of the Zn-Coordinated N-Oxides with Pyrene
Mixing zinc(II) chloride and NPO in acetone (in a 10:1 molar ratio) resulted in the formation of essentially colorless crystals (1) comprising ZnCl 2 and N-oxide in a 1:1 ratio.Each zinc(II) ion coordinates two oxygen atoms from two NPO molecules.In turn, each oxygen is coordinated to two zinc(II) ions.Such bonding produced centrosymmetric 2:2 adducts forming 4-membered rings (Figure 2).They comprised pairs of two non-equivalent Zn-O bonds of 2.002 Å and 2.348 Å (the latter is shown as a dash-dotted line in Figure 2).Besides the coordination of two oxygens, each zinc(II) ion coordinates three Cl − anions.Two of them are shared by two zinc ions.The Zn-Cl bond lengths with these bridging chlorides (2.403 Å) are noticeably higher than that of chloride coordinated with just one zinc (2.215 Å).Overall, zinc(II) is characterized by distorted trigonal-bipyramidal geometry which is rather rare for these ions.
BF3-coordinated NPO and NQO molecules, and they were related to the formation of charge-transfer complexes between BF3-coordinated NPO or NQO and pyrene.These complexes showed absorption bands in the 500-600 nm range (which are red-shifted as compared to those of the corresponding complexes with individual N-oxides) [8].TD DFT calculations indicated the presence of equivalent low-energy absorption bands for the complexes of protonated and Zn(II)-coordinated NQO (Table S1 in the Supporting Information).However, the presence of uncoordinated N-oxides in the solution with the highest concentrations of ZnCl2 together with the low solubility of pyrene in solvents suitable for the dissolution of zinc chloride precluded a quantitative UV-Vis spectral measurements of the interaction of Zn-coordinated N-oxides with pyrene.As such, the new absorption band of such complexes was observed only in the solutions of protonated NQO (Figure S4 in the Supporting Information).Overall, the liquid-phase studies indicated that despite the presence of an electron-withdrawing substituent, NPQ and NQO form complexes with ZnCl2, and the presence of the latter affects the interaction between N-oxides and pyrene in a similar way as boron trifluoride.

X-ray Structural Studies of the Associations of the Zn-Coordinated N-Oxides with Pyrene
Mixing zinc(II) chloride and NPO in acetone (in a 10:1 molar ratio) resulted in the formation of essentially colorless crystals (1) comprising ZnCl2 and N-oxide in a 1:1 ratio.Each zinc(II) ion coordinates two oxygen atoms from two NPO molecules.In turn, each oxygen is coordinated to two zinc(II) ions.Such bonding produced centrosymmetric 2:2 adducts forming 4-membered rings (Figure 2).They comprised pairs of two non-equivalent Zn-O bonds of 2.002 Å and 2.348 Å (the latter is shown as a dash-dotted line in Figure 2).Besides the coordination of two oxygens, each zinc(II) ion coordinates three Cl − anions.Two of them are shared by two zinc ions.The Zn-Cl bond lengths with these bridging chlorides (2.403 Å) are noticeably higher than that of chloride coordinated with just one zinc (2.215 Å).Overall, zinc(II) is characterized by distorted trigonal-bipyramidal geometry which is rather rare for these ions.Crystallization from solutions containing ZnCl2 and NPO (in 1:2 molar ratio) together with a large excess of pyrene resulted in the formation of red triclinic crystals of Crystallization from solutions containing ZnCl 2 and NPO (in 1:2 molar ratio) together with a large excess of pyrene resulted in the formation of red triclinic crystals of [ZnCl 2 (NPO) 2 ] 2 (pyrene) 5 (2).They comprised zinc ions coordinated to two Cl − anions and two NPO molecules.Notably, such coordination of two N-oxides to zinc(II) halides and the tetrahedral geometry of the [ZnCl 2 (NPO) 2 ] complex represents a common motif in the associations of zinc(II) halides with various N-oxides [24][25][26][27], as opposed to the rare 2:2 Zn:NPO binding and trigonal-bipyramidal geometry of zinc complexes in 1.The most im-portant for the current work was the fact that crystal 2 contains pyrene in a 2:5 zinc-pyrene ratio.Two NPO molecules from two [ZnCl 2 (NPO) 2 ] complexes form π-stacked ternary units with one pyrene molecule in the center.This ternary complex shows multiple contacts between the essentially co-planar NPO and pyrene molecules (Figure 3 and Figure S5 in the Supporting Information).The remaining NPO molecules from the two zinc complexes are located on the opposite sides of the ternary complex.Each of these N-oxides forms 1:1 complexes with pyrene.However, in contrast to the ternary associations, there is only one contact shorter than the van der Waals separation in each of these π-stacked dyads.These stacks are separated by pyrene molecules which do not interact with the N-oxides (Figure S5 in the Supporting Information).
[ZnCl2(NPO)2]2(pyrene)5 (2).They comprised zinc ions coordinated to two Cl − anions and two NPO molecules.Notably, such coordination of two N-oxides to zinc(II) halides and the tetrahedral geometry of the [ZnCl2(NPO)2] complex represents a common motif in the associations of zinc(II) halides with various N-oxides [24][25][26][27], as opposed to the rare 2:2 Zn:NPO binding and trigonal-bipyramidal geometry of zinc complexes in 1.The most important for the current work was the fact that crystal 2 contains pyrene in a 2:5 zincpyrene ratio.Two NPO molecules from two [ZnCl2(NPO)2] complexes form π-stacked ternary units with one pyrene molecule in the center.This ternary complex shows multiple contacts between the essentially co-planar NPO and pyrene molecules (Figure 3 and Figure S5 in the Supporting Information).The remaining NPO molecules from the two zinc complexes are located on the opposite sides of the ternary complex.Each of these N-oxides forms 1:1 complexes with pyrene.However, in contrast to the ternary associations, there is only one contact shorter than the van der Waals separation in each of these π-stacked dyads.These stacks are separated by pyrene molecules which do not interact with the Noxides (Figure S5 in the Supporting Information).Crystallization from the solutions of ZnCl2 with another N-oxide, NQO, and an excess of pyrene resulted in the formation of also red co-crystals of [(NQO)2ZnCl2]2(pyrene)3 (3) comprising π-π bonded associations between the pyrene and zinc-coordinated N-oxide molecules (Figure 4).These associations represent the centrosymmetric heptameric complexes consisting of alternating (and essentially co-planar) four N-oxides and three pyrene molecules.Each pyrene molecule in the heptamer forms one or several contacts (on both sides) with NQO molecules that are shorter than van der Waals separation.The terminal NQO molecules in one heptamer neighbor similar molecules in the other heptamers with two short contacts between oxygens in the nitro groups of one NQO and with a carbon atom in the quinoline core of its neighbor.Crystallization from the solutions of ZnCl 2 with another N-oxide, NQO, and an excess of pyrene resulted in the formation of also red co-crystals of [(NQO) 2 ZnCl 2 ] 2 (pyrene) 3 (3) comprising π-π bonded associations between the pyrene and zinc-coordinated N-oxide molecules (Figure 4).These associations represent the centrosymmetric heptameric complexes consisting of alternating (and essentially co-planar) four N-oxides and three pyrene molecules.Each pyrene molecule in the heptamer forms one or several contacts (on both sides) with NQO molecules that are shorter than van der Waals separation.The terminal NQO molecules in one heptamer neighbor similar molecules in the other heptamers with two short contacts between oxygens in the nitro groups of one NQO and with a carbon atom in the quinoline core of its neighbor.
Crystallization of the similar mixtures of ZnCl 2 , NQO, and pyrene from solutions containing THF produced dark red (nearly black) crystals of [ZnCl 2 (THF)(NQO)] 2 (pyrene) 3 (4).Each zinc ion is coordinated with one NQO and one solvent molecule in these co-crystals (Figure 5).Each N-oxide in turn forms a 1: 1 complex with pyrene.Two contacts between essentially co-planar donor and acceptor (with an angle of 5.4 • between the planes of these molecules) were shorter than the van der Waals separations.The [ZnCl 2 (THF)(NQO)]pyrene associations are separated by another (non-bonded) pyrene.
To compare the effects of coordination to metal ions with those resulting from halogen bonding, we also tried to prepare the associations of pyrene with halogen-bonded N-oxide molecules.However, crystallization from solutions containing pyrene and NPO together with a strong halogen-bond donor, diiodine, produced co-crystals (I 9 − )(NPO-H + -NPO)(pyrene) (5) containing pairs of hydrogen-bonded N-oxide molecules (Figure 6).Crystallization of the similar mixtures of ZnCl2, NQO, and pyrene from solutions containing THF produced dark red (nearly black) crystals of [ZnCl2(THF)(NQO)]2(pyrene)3 (4).Each zinc ion is coordinated with one NQO and one solvent molecule in these co-crystals (Figure 5).Each N-oxide in turn forms a 1: 1 complex with pyrene.Two contacts between essentially co-planar donor and acceptor (with an angle of 5.4° between the planes of these molecules) were shorter than the van der Waals separations.The [ZnCl2(THF)(NQO)]pyrene associations are separated by another (non-bonded) pyrene.Crystallization of the similar mixtures of ZnCl2, NQO, and pyrene from solutions containing THF produced dark red (nearly black) crystals of [ZnCl2(THF)(NQO)]2(pyrene)3 (4).Each zinc ion is coordinated with one NQO and one solvent molecule in these co-crystals (Figure 5).Each N-oxide in turn forms a 1: 1 complex with pyrene.Two contacts between essentially co-planar donor and acceptor (with an angle of 5.4° between the planes of these molecules) were shorter than the van der Waals separations.The [ZnCl2(THF)(NQO)]pyrene associations are separated by another (non-bonded) pyrene.To compare the effects of coordination to metal ions with those resulting from halogen bonding, we also tried to prepare the associations of pyrene with halogen-bonded Noxide molecules.However, crystallization from solutions containing pyrene and NPO together with a strong halogen-bond donor, diiodine, produced co-crystals (I9 -)(NPO-H + -NPO)(pyrene) (5) containing pairs of hydrogen-bonded N-oxide molecules (Figure 6).The proton that links two NPO molecules is disordered between two positions (i.e., between bonding to one oxygen and hydrogen bonding to another, and vice versa; note that the crystallographic database contains several similar hydrogen-bonded pairs of Noxide molecules [29][30][31]).The charge of the proton in these crystals is balanced by an iodide anion which forms two stronger and two weaker halogen bonds with four diiodine molecules (with halogen bond lengths of 3.181 Å, 3.451 Å, and 3. 518 Å, see Figure S6 in the Supporting Information).These co-crystals also contain pyrene molecules.Each pyrene is sandwiched between two NPO molecules.These ternary associations comprise multiple contacts between pyrene and NPO that are shorter than the van der Waals separations.
The selected geometric characteristics of the complexes of N-oxides with ZnCl2 and pyrene are listed in Table 1.For comparison, this table also contains the related characteristics of the complexes with the protonated N-oxides as well as reported earlier ternary complexes with boron trifluoride.The proton that links two NPO molecules is disordered between two positions (i.e., between bonding to one oxygen and hydrogen bonding to another, and vice versa; note that the crystallographic database contains several similar hydrogen-bonded pairs of N-oxide molecules [29][30][31]).The charge of the proton in these crystals is balanced by an iodide anion which forms two stronger and two weaker halogen bonds with four diiodine molecules (with halogen bond lengths of 3.181 Å, 3.451 Å, and 3. 518 Å, see Figure S6 in the Supporting Information).These co-crystals also contain pyrene molecules.Each pyrene is sandwiched between two NPO molecules.These ternary associations comprise multiple contacts between pyrene and NPO that are shorter than the van der Waals separations.
The selected geometric characteristics of the complexes of N-oxides with ZnCl 2 and pyrene are listed in Table 1.For comparison, this table also contains the related characteristics of the complexes with the protonated N-oxides as well as reported earlier ternary complexes with boron trifluoride.The data in Table 1 show that the Zn-O bond lengths in the associations with pyrene are close to those reported earlier in the complexes of zinc(II) with other N-oxides (about 2.00 Å [24][25][26][27]) and a shorter Zn-O bond in crystal 1. Coordination with Zn(II) resulted in the increase in the N-O bond lengths in the N-oxides to around 1.33 Å, as compared to about 1.29 Å reported for the individual molecules [34,35].The C-N bonds in the Lewis acid-bonded N-oxides were also elongated to 1.47-1.48Å as compared to 1.46 Å measured in the individual molecules.The N-O distance in the (partially) protonated NPO was slightly longer than that in the complexes with zinc, and complexes with BF 3 showed even longer N-O and C-N bonds.Most notably, all the N-oxide molecules in all of these cocrystals formed π-stacked 1:1 or higher order associations with pyrene with short contacts between the essentially co-planar molecules.This suggests a substantial bonding between pyrene and the Lewis acid-coordinated N-oxides.To confirm the presence of such bonding, we carried out the quantum theory of atoms in molecules (QTAIM) and non-covalent interaction (NCI) analyses of these co-crystals [36][37][38].The QTAIM analyses revealed that all the associations comprise multiple bond paths with the corresponding bond critical points between the N-oxide and pyrene molecules (Figure 7).
the increase in the N-O bond lengths in the N-oxides to around 1.33 Å, as compa about 1.29 Å reported for the individual molecules [34,35].The C-N bonds in the acid-bonded N-oxides were also elongated to 1.47-1.48Å as compared to 1.46 Å me in the individual molecules.The N-O distance in the (partially) protonated NP slightly longer than that in the complexes with zinc, and complexes with BF3 showe longer N-O and C-N bonds.Most notably, all the N-oxide molecules in all of th crystals formed π-stacked 1:1 or higher order associations with pyrene with short c between the essentially co-planar molecules.This suggests a substantial bonding b pyrene and the Lewis acid-coordinated N-oxides.To confirm the presence of such ing, we carried out the quantum theory of atoms in molecules (QTAIM) and non-co interaction (NCI) analyses of these co-crystals [36][37][38].The QTAIM analyses reveal all the associations comprise multiple bond paths with the corresponding bond points between the N-oxide and pyrene molecules (Figure 7).The NCI analyses also showed green-blue areas around each BCP indicatin tively weak attractive interactions.This indicates multicenter bonding between the ides and pyrenes in these associations.To evaluate the strength of these interactio the effects of zinc (and other Lewis acids) on these interactions, we carried out a c tational analysis of these bondings as follows.

Computational Analysis of Complexes of Pyrene with N-oxides
The structures of the individual donor-acceptor associations produced by th mization of the Zn(II)-or BF3-coordinated or protonated N-oxides and their com with pyrene are illustrated in Figure 8.The NCI analyses also showed green-blue areas around each BCP indicating relatively weak attractive interactions.This indicates multicenter bonding between the N-oxides and pyrenes in these associations.To evaluate the strength of these interactions and the effects of zinc (and other Lewis acids) on these interactions, we carried out a computational analysis of these bondings as follows.

Computational Analysis of Complexes of Pyrene with N-oxides
The structures of the individual donor-acceptor associations produced by the optimization of the Zn(II)-or BF 3 -coordinated or protonated N-oxides and their complexes with pyrene are illustrated in Figure 8.
Overall, the structural features of these complexes are consistent with the results of the X-ray structural analysis.In particular, the Zn-O distances in the optimized complexes are essentially the same (about 2.01 Å) as in the solid-state structures.Also, the coordination (or protonation) led to a substantial elongation of the N-O bonds in the N-oxides (Table 2).Most important for the current work, however, were the effects of the interaction with the Lewis acids on the electronic structures of the N-oxides and their interaction with pyrene.Overall, the structural features of these complexes are consistent with the r the X-ray structural analysis.In particular, the Zn-O distances in the optimized co are essentially the same (about 2.01 Å) as in the solid-state structures.Also, the c tion (or protonation) led to a substantial elongation of the N-O bonds in the N (Table 2).Most important for the current work, however, were the effects of the int with the Lewis acids on the electronic structures of the N-oxides and their interact pyrene.All the optimized complexes showed π-stacked N-oxides and pyrene moiet multiple interatomic contacts which were shorter than the sums of the van der Wa Notably, these distances in the complexes of pyrene with Zn-coordinated N-oxid slightly shorter than those in the associations involving non-coordinated accepto  All the optimized complexes showed π-stacked N-oxides and pyrene moieties with multiple interatomic contacts which were shorter than the sums of the van der Waals radii.Notably, these distances in the complexes of pyrene with Zn-coordinated N-oxides were slightly shorter than those in the associations involving non-coordinated acceptors.This indicates that coordination with zinc leads to a stronger attraction between N-oxides and pyrene.These structural indications were confirmed by the comparison of the binding energies, ∆E b .The ∆E b values listed in the last column in Table 2 reveal that the coordination of N-oxides with zinc increases the stability of their π-π bonded complexes.The binding of N-oxides with BF 3 or their protonation led to similar effects.In all the cases, the magnitudes of the binding energies are higher than those found for the individual N-oxide molecules.The free energies of the formation of the complexes with pyrene, ∆G, show similar trends.However, due to the entropy loss during complex formation, these values are much less negative.

Origin of the Lewis Acid Effects on the Multicenter Donor-Acceptor Bonding
The classic Mulliken theory explained the formation of the complexes, such as that between pyrene and N-oxide, in terms of the mixing of the highest occupied molecular orbital (HOMO) of the electron donor with the lowest unoccupied orbital of the acceptor (LUMO), resulting in partial charge transfer [39].The stability of such complexes is determined, in part, by the HOMO/LUMO gap of the interacting species.As such, an increase in its electron-acceptor strength (i.e., the lowering of the LUMO energy of the acceptor) in the complexes with the same donor results in more stable complexes.In comparison, the σ-and π-hole concepts which were developed during the last two decades relate the formation of the supramolecular complexes to the electrostatic attraction of electron-rich species to the areas of the positive potential on the surfaces of electron acceptors [40].However, while the σ-and π-hole concepts were extensively utilized in the analysis of the recently recognized types of supramolecular interactions (e.g., halogen, chalcogen, or anion-π bondings), their applications for the π-stacked donor-acceptor complexes are scarce.
The maps of the surface electrostatic potentials of pyrene and individual and Lewis acid-coordinated N-oxides are shown in Figure 9 and Figure S7 in the Supporting Information.These maps revealed that the area over the aromatic core of the pyrene is characterized by negative potentials, and its side (the area along the extension of the C-H bond) shows positive potential.
magnitudes of the binding energies are higher than those found for the individual N-oxide molecules.The free energies of the formation of the complexes with pyrene, ΔG, show similar trends.However, due to the entropy loss during complex formation, these values are much less negative.

Origin of the Lewis acid Effects on the Multicenter Donor-Acceptor Bonding
The classic Mulliken theory explained the formation of the complexes, such as that between pyrene and N-oxide, in terms of the mixing of the highest occupied molecular orbital (HOMO) of the electron donor with the lowest unoccupied orbital of the acceptor (LUMO), resulting in partial charge transfer [39].The stability of such complexes is determined, in part, by the HOMO/LUMO gap of the interacting species.As such, an increase in its electron-acceptor strength (i.e., the lowering of the LUMO energy of the acceptor) in the complexes with the same donor results in more stable complexes.In comparison, the σ-and π-hole concepts which were developed during the last two decades relate the formation of the supramolecular complexes to the electrostatic attraction of electron-rich species to the areas of the positive potential on the surfaces of electron acceptors [40].However, while the σ-and π-hole concepts were extensively utilized in the analysis of the recently recognized types of supramolecular interactions (e.g., halogen, chalcogen, or anionπ bondings), their applications for the π-stacked donor-acceptor complexes are scarce.
The maps of the surface electrostatic potentials of pyrene and individual and Lewis acid-coordinated N-oxides are shown in Figure 9 and Figure S7 in the Supporting Information.These maps revealed that the area over the aromatic core of the pyrene is characterized by negative potentials, and its side (the area along the extension of the C-H bond) shows positive potential.The most positive potentials on the surface of N-oxides are also located over their hydrogen substituents.However, N-oxides show two areas of positive potential over their molecular framework, i.e., π-holes, above the pyridinium ring center and C-NO2 fragment.The latter potential is somewhat larger in the individual NPO and NQO molecules (Table 2), and the coordination of NPO or NQO to Zn(II) increases the magnitude of both of these π-holes (similar to the enhancement of the π-holes over the C-NO2 fragment of NPO resulting from the halogen or hydrogen bonding of this N-oxide or its coordination to BF3 reported by Frontera et al. [15]).Thus, the increase in the magnitude of ΔE in the complexes with coordinated or protonated N-oxides as compared to that in the individual acceptors can be related to the increase in the potential of the π-holes.This implies that the electrostatic attraction between the areas of the negative potentials on the surface of The most positive potentials on the surface of N-oxides are also located over their hydrogen substituents.However, N-oxides show two areas of positive potential over their molecular framework, i.e., π-holes, above the pyridinium ring center and C-NO 2 fragment.The latter potential is somewhat larger in the individual NPO and NQO molecules (Table 2), and the coordination of NPO or NQO to Zn(II) increases the magnitude of both of these π-holes (similar to the enhancement of the π-holes over the C-NO 2 fragment of NPO resulting from the halogen or hydrogen bonding of this N-oxide or its coordination to BF 3 reported by Frontera et al. [15]).Thus, the increase in the magnitude of ∆E in the complexes with coordinated or protonated N-oxides as compared to that in the individual acceptors can be related to the increase in the potential of the π-holes.This implies that the electrostatic attraction between the areas of the negative potentials on the surface of pyrene with the areas of the positive potential over the pyridinium ring and the C-NO 2 fragments of N-oxides plays a significant role in the formation of the π-stacked complexes.However, the correlation between ∆E and V π holes is rather weak (they are characterized by the R 2 values of 0.67 and 0.77 for the complexes with NQO and NPO, respectively, and 0.53 if all the complexes are considered in a single correlation; see Figure S8 in the Supporting Information).Also, the binding of pyrene with NQO is stronger than that with NPO, even though the V π hole values on the surface of the latter are higher.Apparently, besides electrostatics, other factors contribute to the binding between N-oxides and pyrene.Since the NQO surface is larger, dispersion probably represents one of the factors leading to the stronger binding of this molecule with pyrene.Another factor could be related to the molecular orbital interactions.Specifically, the energy of LUMO of NQO is lower.According to the Mulliken theory [39], this leads to higher donor-acceptor charge transfer and stronger binding.Natural Bond Orbital (NBO) analysis confirmed that charge transfer from pyrene to NQO is slightly larger than to NPO.Furthermore, coordination to zinc, BF 3 , or protonation substantially decreases the energies of the LUMOs of NPO and NQO, and the correlation between the energies of LUMO and ∆E (with R 2 = 0.68 for all the complexes; see Figure S8 in the Supporting Information) is somewhat better than that between ∆E and V π hole (it should be mentioned, though, that the variation in the LUMOs' energies is correlated with the values of V π holes , which hinders the separation of the effects of these two factors).Moreover, earlier studies showed that the interaction of various aromatic donors (including pyrene) with BF 3 -coordinated NQO molecules led to the appearance of a new absorption band of the complex that followed the Mulliken correlation [8].These observations suggest the significant contribution of molecular-orbital (charge-transfer) interactions in the formation of these complexes.
To quantify the contributions of the electrostatic and molecular-orbital interactions, as well as dispersion to the bonding between N-oxides and pyrene, we carried out an energydecomposition analysis (EDA) of interaction energies in these associations.In particular, the EDA analysis using the AMS suite of programs decomposes the intermolecular interaction energy values into its electrostatic, ∆E elstat ; Pauli repulsion, ∆E Pauli ; orbital (charge-transfer) interaction, ∆E oi ; and dispersion, ∆E disp components: [41,42] The values of the interaction energies and their components for the complexes of pyrene with Zn(II)-or BF 3 -coordinated and individual N-oxides are listed in Table 3. a note that values for the positively charged complex with the protonated N-oxides showed similar trends, but only data for the neutral complexes are shown for consistent comparison.
The data in Table 3 show that coordination to ZnCl 2 or BF 3 increases all three components of the attractive interaction.These increases are compensated, to some extent, by the increase in the Pauli repulsion (due to the closer approach of the interacting molecules).As such, none of the individual attractive components (i.e., ∆E elstat , ∆E oi , or ∆E disp ) would be sufficient, if taken separately, to account for the increase in the magnitude of the interaction energy.
In conclusion, our results indicate that the effects of the Lewis acid on the multicenter donor-acceptor bonding are related both to the enhancement of the π-holes on the surface of the N-oxides and the strengthening of their electron-acceptor properties (as reflected in the lower energies of their LUMOs).These factors lead to the increase in the magnitudes of the (attractive) electrostatic and orbital interactions, which bring donor and acceptor closer together and further enhance dispersion interaction as well as Pauli repulsion.The combination of all these components produces a stronger π-π binding of N-oxides and a model π-donor, pyrene.

Materials and Methods
Commercially available ZnCl 2 , NQO, and pyridine-N-oxide (all from Sigma Aldrich, St. Louis, MO, USA), as well as NPO and 4-methoxypyridine-N-oxide (all from TCI, Tokyo, Japan) were used without additional purification.The UV-Vis measurements were carried out on a Cary 5000 spectrophotometer (Agilent, Santa Clara, CA, USA) as described before [8,14].
Single crystals 1 of the Zn(II)-coordinated NPO were prepared by the dissolution of N-oxide in acetone and adding a 10-fold excess of ZnCl 2 .After the removal of the remaining undissolved material (by centrifuging), the solution was placed in a refrigerator (4 • C).Essentially colorless crystals 1 containing ZnCl 2 and NPO were formed after 24 h.Co-crystals containing Zn-coordinated nitropyridine-N-oxide and pyrene were prepared by mixing ZnCl 2 and NPO in a 1:2 molar ratio together with a ten-fold excess of pyrene in dichloromethane.This mixture was cooled down to −20 • C and kept at this temperature for several weeks.During this time, red crystals of [ZnCl 2 (NPO) 2 ] 2 (pyrene) 5 (2) were formed.A similar procedure with NQO instead of NPO produced crystals [ZnCl 2 (NQO) 2 ] 2 (pyrene) 3 (3).The crystallization of analogous three-components mixture from dichloromethanetetrahydrofuran (1:1) solution produced [ZnCl 2 (THF)(NQO)] 2 (pyrene) 3 crystals (4).Crystals 5 were prepared by mixing NPO, pyrene, and diiodine in a 1:1:1 molar ratio in dichloromethane.This mixture was cooled down to −30 • C and kept at this temperature in an open vial for several weeks.This resulted in the formation of dark crystals 5, (I 9 − )(NPO-H + -NPO)(pyrene).Note that due to the limited solubility of N-oxides and pyrene, the crystals of the complexes were obtained as mixtures with the crystals of the individual components.Also, multiple attempts to prepare single crystals of ZnCl 2 (NQO) (using various solvents and conditions) resulted in the precipitation of the individual NQO.This is related to the limited solubility of NQO in the solvents suitable for the dissolution of ZnCl 2 and the low formation constants of the complex formation.The formation of the ternary complexes in the presence of pyrene indicates (in agreement with [15]) that bonding with pyrene facilitates coordination to zinc, and vice versa.
The single crystal structures were determined on a Bruker Quest diffractometer (Bruker AXS, LLC, Madison, WI, USA) with a fixed chi angle, a sealed tube fine focus X-ray tube, a single crystal curved graphite incident beam monochromator, a PhotonII area detector (Bruker AXS, LLC, Madison, WI, USA), and an Oxford Cryosystems low temperature device (Oxford Cryosystems, Oxford OX29 8LH, United Kingdom).The examination and data collection were performed with Mo Kα radiation (λ = 0.71073 Å).The reflections were indexed and processed, and the files were scaled and corrected for absorption using APEX4 [43].The space groups were assigned using XPREP within the SHELXTL suite of programs, and the structures were solved by dual methods using ShelXT and refined by full-matrix least-squares against F 2 with all the reflections using the graphical interface Shelxle [44][45][46][47].If not specified otherwise, the H atoms attached to carbon atoms were positioned geometrically and constrained to ride on their parent atoms, with the C-H bond distances of 1.00, 0.99, and 0.98 Å for aliphatic CH 2 moieties, respectively.The methyl H atoms were allowed to rotate but not to tip to best fit the experimental electron density.The U iso (H) values were set to a multiple of U eq (C) with 1.5 for CH 3 and 1.2 for C-H units, respectively.Crystallographic, data collection, and refinement details are listed in Table S2 in the Supplementary Materials.Complete crystallographic data, in CIF format, have been deposited with the Cambridge Crystallographic Data Centre.CCDC 2358284-2358287 and 2365181 contain the supplementary crystallographic data for this paper.These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif.
The geometries of the complexes and their components were optimized without constraints via M06-2X/6-31G* calculations (in dichloromethane, with a polarizable continuum model) using the Gaussian 09 suite of programs [48][49][50].The absence of imaginary frequen-

Figure 1 .
Figure 1.Spectra of acetonitrile solutions with constant concentrations of NPO (2.7 mM, left) and pyridine-N-oxide (5.6 mM, right) and various concentrations of ZnCl2.The spectra of the solutions of individual N-oxides are shown as dashed red lines (the absorption of ZnCl2 is negligible in this range).

Figure 1 .
Figure 1.Spectra of acetonitrile solutions with constant concentrations of NPO (2.7 mM, left) and pyridine-N-oxide (5.6 mM, right) and various concentrations of ZnCl 2 .The spectra of the solutions of individual N-oxides are shown as dashed red lines (the absorption of ZnCl 2 is negligible in this range).

Figure 6 .
Figure 6.Fragment of the X-ray structure (view along an a axis) of co-crystals (I9 -)(NPO-H + -NPO)(pyrene) (5) containing hydrogen-bonded pairs of NPO and pyrene (the halogen-bonded nonaiodide network is omitted for clarity; it is shown in Figure S6 in the Supporting Information).Light blue lines show contacts shorter than the van der Waals separations.Color code: dark graycarbon, light gray-hydrogen, red-oxygen, and blue-nitrogen.

Figure 6 .
Figure 6.Fragment of the X-ray structure (view along an a axis) of co-crystals (I 9 − )(NPO-H + -NPO)(pyrene) (5) containing hydrogen-bonded pairs of NPO and pyrene (the halogen-bonded nonaiodide network is omitted for clarity; it is shown in Figure S6 in the Supporting Information).Light blue lines show contacts shorter than the van der Waals separations.Color code: dark graycarbon, light gray-hydrogen, red-oxygen, and blue-nitrogen.

a
Electrostatic potentials over the pyridinium ring and the C-NO2 fragment (vide infra); b E the LUMOs; c N-O bond lengths in the individual or Lewis acid-bonded N-oxide.The parenthesis show the bond length in the corresponding complexes with pyrene; d Binding between pyrene and (individual or coordinated) N-oxide; e Free energy change in com mation; f Charge transfer from pyrene.

Table 1 .
Selected distances (in Å) in the co-crystals of N-oxides with pyrene.
[8]n-O or B-O distances; b N-oxide group; c aromatic carbon to nitrogen of nitro group; d shortest interatomic distance between N-oxide and pyrene; e from[8].

Table 1 .
Selected distances (in Å) in the co-crystals of N-oxides with pyrene.

Table 2 .
Selected characteristics of the optimized individual or Lewis acid-bonded N-ox their complexes with pyrene.

Table 2 .
Selected characteristics of the optimized individual or Lewis acid-bonded N-oxides and their complexes with pyrene.
a Electrostatic potentials over the pyridinium ring and the C-NO 2 fragment (vide infra); b Energy of the LUMOs; c N-O bond lengths in the individual or Lewis acid-bonded N-oxide.The values in parenthesis show the bond length in the corresponding complexes with pyrene; d Binding energies between pyrene and (individual or coordinated) N-oxide; e Free energy change in complex formation; f Charge transfer from pyrene.

Table 3 .
Component of interaction energy (in kcal/mol) in the complexes of N-oxides with pyrene (from the EDA analysis).